An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• Tubulin, a key component of microtubules, is a validated anti-cancer drug target.
• Drug resistance in human beta-tubulin arises from amino acid substitutions, necessitating novel therapeutic approaches.

Purpose of the Study:

• To investigate the impact of specific amino acid substitutions (F270V, A364T, Q292E) in human beta-tubulin on drug binding.
• To identify potential drug candidates from plant and marine sources that can overcome tubulin-based drug resistance.

Main Methods:

• Generated three human beta-tubulin mutants (F270V, A364T, Q292E) using Modeller9v10.
• Screened compounds from higher plants, lower plants, and marine isolates for interactions with tubulin mutants using iGEMDOCK2.0.

Main Results:

• The F270V mutation showed conservative substitutions, increasing active site volume but not binding affinity compared to the taxol-wild type.
• The A364T mutation improved binding with some marine and higher plant compounds due to polar residue substitution, but reduced active site volume.
• The Q292E mutation, located in the epothilone binding site, significantly altered drug binding compared to the wild type due to substitution of an uncharged with a charged residue, without changing active site volume.

Conclusions:

• Lower plant extracts demonstrated favorable interactions with both taxol and epothilone binding sites.
• Marine and higher plant isolates showed significant interactions with wild-type tubulin but not with the generated mutants.
• Amino acid substitutions in tubulin mutants were observed to alter active site conformations, influencing drug interactions.